Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis
Abstract Despite substantial advances in the antitumor effects of annonaceous acetogenins (ACGs), the absence of a defined biological action mechanism remains a major barrier to their clinical application. Here, it is found that squamocin effectively depletes both EZH2 and MYC in multiple cancer cel...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202413120 |
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| author | Yin Zhu Yurui Liu Xiangtao Wang Zhifeng Chen Baojian Chen Bingxin Hu Tiane Tang Haoran Cheng Xinglong Liu Yunshan Ning |
| author_facet | Yin Zhu Yurui Liu Xiangtao Wang Zhifeng Chen Baojian Chen Bingxin Hu Tiane Tang Haoran Cheng Xinglong Liu Yunshan Ning |
| author_sort | Yin Zhu |
| collection | DOAJ |
| description | Abstract Despite substantial advances in the antitumor effects of annonaceous acetogenins (ACGs), the absence of a defined biological action mechanism remains a major barrier to their clinical application. Here, it is found that squamocin effectively depletes both EZH2 and MYC in multiple cancer cell lines, including head and neck squamous cell carcinoma, and gastric and colorectal cancer, demonstrating potent efficacy in suppressing these in vivo tumor models. Through the combination of surface plasmon resonance (SPR), differential scanning fluorimetry (DSF), and cellular thermal shift assay (CETSA), heat shock protein 90α (HSP90α) is identified as the direct binding target of squamocin. Mechanistically, squamocin disrupts mitochondrial respiratory Complex I function, reduces ATP production, and impairs HSP90α function, provoking endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). These intrinsic events within tumor cells enhance ER stress‐associated ubiquitylation and degradation by triggering ubiquitin via the E1 activase UBA6, facilitating ubiquitin transferring to E2 conjugate UBE2Z and increasing the activities of E3 ligase FBXW7 to degrade both EZH2 and MYC. The findings elucidate the role of squamocin in the degradation of oncoproteins EZH2 and MYC by triggering an ER stress‐associated UBA6‐UBE2Z‐FBXW7 ubiquitin cascade, providing insights that may accelerate therapeutic development targeting tumors driven by the EZH2/MYC axis. |
| format | Article |
| id | doaj-art-86a026ff7f9a4d2aa94970cb58efbee3 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-86a026ff7f9a4d2aa94970cb58efbee32025-08-20T02:17:28ZengWileyAdvanced Science2198-38442025-04-011215n/an/a10.1002/advs.202413120Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC AxisYin Zhu0Yurui Liu1Xiangtao Wang2Zhifeng Chen3Baojian Chen4Bingxin Hu5Tiane Tang6Haoran Cheng7Xinglong Liu8Yunshan Ning9School of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaSchool of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaInstitute of Medicinal Plant Development Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100193 ChinaDepartment of Stomatology Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaSouthern Medical University Hospital of Integrated Traditional Chinese and Western Medicine Southern Medical University Guangzhou 510000 ChinaSchool of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaSchool of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaThe First Clinical Medical School Southern Medical University Guangzhou 510515 ChinaSchool of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaSchool of Laboratory Medicine and Biotechnology Southern Medical University Guangzhou 510515 ChinaAbstract Despite substantial advances in the antitumor effects of annonaceous acetogenins (ACGs), the absence of a defined biological action mechanism remains a major barrier to their clinical application. Here, it is found that squamocin effectively depletes both EZH2 and MYC in multiple cancer cell lines, including head and neck squamous cell carcinoma, and gastric and colorectal cancer, demonstrating potent efficacy in suppressing these in vivo tumor models. Through the combination of surface plasmon resonance (SPR), differential scanning fluorimetry (DSF), and cellular thermal shift assay (CETSA), heat shock protein 90α (HSP90α) is identified as the direct binding target of squamocin. Mechanistically, squamocin disrupts mitochondrial respiratory Complex I function, reduces ATP production, and impairs HSP90α function, provoking endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). These intrinsic events within tumor cells enhance ER stress‐associated ubiquitylation and degradation by triggering ubiquitin via the E1 activase UBA6, facilitating ubiquitin transferring to E2 conjugate UBE2Z and increasing the activities of E3 ligase FBXW7 to degrade both EZH2 and MYC. The findings elucidate the role of squamocin in the degradation of oncoproteins EZH2 and MYC by triggering an ER stress‐associated UBA6‐UBE2Z‐FBXW7 ubiquitin cascade, providing insights that may accelerate therapeutic development targeting tumors driven by the EZH2/MYC axis.https://doi.org/10.1002/advs.202413120annonaceous acetogeninsendoplasmic reticulum stress responseEZH2/MYC axissquamocinubiquitin‐proteasome degradation system |
| spellingShingle | Yin Zhu Yurui Liu Xiangtao Wang Zhifeng Chen Baojian Chen Bingxin Hu Tiane Tang Haoran Cheng Xinglong Liu Yunshan Ning Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis Advanced Science annonaceous acetogenins endoplasmic reticulum stress response EZH2/MYC axis squamocin ubiquitin‐proteasome degradation system |
| title | Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis |
| title_full | Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis |
| title_fullStr | Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis |
| title_full_unstemmed | Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis |
| title_short | Squamocin Suppresses Tumor Growth through Triggering an Endoplasmic Reticulum Stress‐Associated Degradation of EZH2/MYC Axis |
| title_sort | squamocin suppresses tumor growth through triggering an endoplasmic reticulum stress associated degradation of ezh2 myc axis |
| topic | annonaceous acetogenins endoplasmic reticulum stress response EZH2/MYC axis squamocin ubiquitin‐proteasome degradation system |
| url | https://doi.org/10.1002/advs.202413120 |
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